Oncogenesis was described by Foulds (1958) as a multistep biological process, which is presently known to occur by the accumulation of genetic damage. On a molecular level, the multistep process of tumorigenesis involves the disruption of both positive and negative regulatory effectors (Weinberg, 1989). The molecular basis for human colon carcinomas has been postulated, by Vogelstein and coworkers (1990), to involve a number of oncogenes, tumor suppressor genes and repair genes. Similarly, defects leading to the development of retinoblastoma have been linked to another tumor suppressor gene (Lee et al., 1987). Still other oncogenes and tumor suppressors have been identified in a variety of other malignancies. Unfortunately, there remains an inadequate number of treatable cancers, and the effects of cancer are catastrophic—over half a million deaths per year in the United States alone.
Cancer is fundamentally a genetic disease in which damage to cellular DNA leads to disruption of the normal mechanisms that control cellular proliferation. Two of the mechanisms of action by which tumor suppressors maintain genomic integrity is by cell arrest, thereby allowing for repair of damaged DNA, or removal of the damaged DNA by apoptosis (Ellisen and Haber, 1998; Evan and Littlewood, 1998). Apoptosis, otherwise called “programmed cell death,” is a carefully regulated network of biochemical events which act as a cellular suicide program aimed at removing irreversibly damaged cells. Apoptosis can be triggered in a number of ways including binding of tumor necrosis factor, DNA damage, withdrawal of growth factors, and antibody cross-linking of Fas receptors. Although several genes have been identified that play a role in the apoptotic process, the pathways leading to apoptosis have not been fully elucidated. Many investigators have attempted to identify novel apoptosis-promoting genes with the objective that such genes would afford a means to induce apoptosis selectively in neoplastic cells to treat cancer in a patient.
An alternative approach to treating cancer involves the suppression of angiogenesis with agent such as Endostatin™ or anti-VEGF antibodies. In this approach, the objective is to prevent further vascularization of the primary tumor and potentially to constrain the size of metastatic lesions to that which can support neoplastic cell survival without substantial vascular growth.
Platelet endothelial cell adhesion molecule (PECAM-1; CD31) is a protein found on endothelial cells and neutrophils and has been shown to be involved in the migration of leukocytes across the endothelium. The modulation of the activity of PECAM-1 for the treatment of cardiovascular conditions such as thrombosis, vascular occlusion stroke and for the treatment of or for reducing the occurrence of haemostasis disorders is disclosed in WO03055516A1. PECAM-1 has also been implicated in the inflammatory process and anti-PECAM-1 monoclonal antibody has been reported to block in vivo neutrophil recruitment (Nakada et al. (2000) J. Immunol. 164: 452-462). PECAM-1 knockout mice have been reported and appear to have normal leukocyte migration, platelet aggregaton, and vascular development, which implies that there are redundant adhesion molecules which can compensate for a loss of PECAM-1 (Duncan et al. (1999) J. Immunol. 162: 3022-3030). Monoclonal antibodies to PECAM-1 have been reported to block murine endothelial tube formation and related indicators of vascularization in a tumor transplantation model (Zhou et al. (1999) Angiogenesis 3: 181-188 and in a human skin transplantation model (Cao et al. (2002) Am. J. Physiol. Cell Physiol. 282: C1181-C1190). However, the role of PECAM-1 in tumor angiogenesis, if any, remains undefined.
Despite substantial efforts to inhibit cancer and the metastasis of tumors with anti-angiogenic strategies, to date there are no approved and marketed drugs for treating cancer solely by the inhibition of angiogenesis. Indeed the specific roles of various adhesion molecules, including PECAM-1, in the processes of neoplasia and metastasis are unknown.
There exists a need in the art for a method and related compositions for inhibiting the metastatic potential of cancer cells in patients. The present invention fulfills this need and provides related aspects desired by practitioners in the field.
The references discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention. All patent and literature publications referenced herein are incorporated by reference for all purposes as if the entire content of the disclosures were mechanically or electronically reproduced herein.